BACKGROUND AND AIMS: Epidemiological studies have revealed the role of lipoprotein(a) [Lp(a)] in the etiopathogenesis of cardiovascular disease (CVD). We analyzed the association between Lp(a) and the risk of a major cardiovascular event in subjects with previous CVD. METHODS: The analysis was conducted on the Moli-sani study population (24,325 individuals aged ≥35 years, recruitment from 2005 to 2010), focusing on subjects with prior CVD. Data from standardized questionnaires and blood pressure, anthropometric, and lab measurements were collected. Lp(a) levels were measured using biobanked samples. The cohort was followed for cardiovascular events. The association between Lp(a) levels and risk of major adverse cardiovascular events was analyzed using Kaplan-Meier and Cox regression models. RESULTS: In total, 1,284 subjects reported a history of CVD at baseline. The mean ± SD Lp(a) level was 23.3 ± 26.0 mg/dl and 51 subjects (4.0%) had levels ≥90 mg/dl. After a median of 7.3 years, 307 CVD events were recorded and validated. Subjects belonging to the highest Lp(a) level group (≥90 mg/dl) showed a worse trend during early follow-up compared with the lowest level group (<30 mg/dl), with a peak during the first 18 months [hazard ratio (HR) = 3.43, 95% confidence interval (CI): 1.43-8.27]. This increase was higher in subjects with dyslipidemia not treated with statins and those with multiple previous CVD events (HR = 11.0, 95% CI: 1.98-61.1; HR = 25.6, 95% CI: 7.83-83.8). CONCLUSIONS: High Lp(a) levels were associated with an increased risk of early secondary cardiovascular events in individuals with a history of multiple CVDs or non-treated dyslipidemia, suggesting that lipoprotein(a) is a modifiable biomarker that can be measured at different times for CVD risk assessment.